Dose- and route-dependent alterations in metabolism and toxicity of chemical compounds in ethanol-treated rats: difference between highly (chloroform) and poorly (carbon tetrachloride) metabolized hepatotoxic compounds.

The dose and route dependency of the metabolism and the toxicity of chloroform (CHCl3) and carbon tetrachloride (CCl4) was investigated in ethanol-treated rats. Rats that had been kept on either an ethanol (containing ethanol at 2 g/rat/day) or a control (containing no ethanol) liquid diet for 3 weeks were challenged with CHCl3 or CCl4 by inhalation (0, 50, or 500 ppm x 6 hr), or by p.o. or i.p. administration (0, 0.105, or 1.675 mmol/kg). Ethanol consumption, which increased the in vitro metabolism of both compounds six- to sevenfold, affected the metabolism and toxicity of CCl4 differently from those of CHCl3. Ethanol increased the metabolism and toxicity of CHCl3 at 500 ppm only, whereas it increased the metabolism and toxicity of CCl4 at either 50 or 500 ppm. In addition, the effect of ethanol consumption differed between CHCl3 and CCl4 depending on the route of administration (p.o. or i.p.) and the dose (0.105 or 1.675 mmol/kg). For the p.o. route, ethanol increased the metabolism and toxicity of both compounds at either dose. For the i.p. route, however, ethanol increased the metabolism and toxicity of the high dose of CHCl3 only, but of both CCl4 doses. The dose- and route-dependent differences in the effect of enzyme induction on the metabolism and toxicity between CHCl3 and CCl4 can be explained by a supposition that the hepatic blood flow rate-limits the metabolism of a low dose of CHCl3 (perfusion-limited metabolism), whereas the metabolic capacity of the liver limits the metabolism of CCl4 (capacity-limited metabolism) irrespective of dose.